Heart failure represents the end-point of the most common forms of heart disease, and its current therapy is at best palliative. The decornpensated stage of heart failure is usually preceded by a chronic, compensatory cardiac hypertrophy. The mechanisms that precipitate the transition from hypertrophy to failure remain largely unknown. This is due in large part to the lack of relevant chronic models that reproduce the clinical conditions. It is our hypothesis that a better understanding of the molecular adaptations to heart failure, both at the gene and protein level, will lead to the development of improved therapy. Our first Aim is to use genomic and proteomic approaches to better define the alterations of the beta-adrenergic signaling pathway during the transition from cardiac hypertrophy to heart failure. We will compare these data to those obtained in our murine models of cardiomyopathy and in myocardial samples from patients with congestive heart failure. Our second Aim will determine whether protein synthesis and degradation is qualitatively and quantitatively altered in heart failure. Specifically, we will measure the activity of ubiquitin and of the proteasome, and we will determine the identity of the proteins degraded by these mechanisms. Our third Aim will be to define the alterations in the expression of novel or unexpected genes in the failing heart, in an attempt to unravel potential novel physiological mechanisms and therapeutic strategies. In summary, the overall theme of this Project is to better understand the pathophysiology of heart failure in a novel model of heart failure superposed on chronic, severe hypertrophy, using a combination of both genomic and proteomic methodologies.